Layering processes involve loading solid inert cores with drugs and/or excipients. Inert cores, placed in a suitable vessel such as a coating pan or a fluid bed, may be layered according to different methods. Some methods consist of spraying onto the cores a solution/suspension containing both drug and binding agent. Others are based on layering the drug directly in powdery form where drug loading occurs by gravity and adhesion is ensured by a liquid binder sprayed onto the cores. Some examples concerning different layering processes are described in the following patents: WO 95/14460, WO 96/01621.
The layering process is particularly suitable for production of small drug loaded units, multiples of which are placed into capsules for patient delivery. In the case of spherical inert cores such as non pareils, the layering techniques from solution/suspensions, produce homogeneous drug loaded particles, which retain an approximately spherical shape. They are therefore particularly suitable for successively film coating to build up the particle with the aim of providing a desired drug release profile. These spraying methods based on liquid applications are very time consuming due to the relative low concentration of the active substance in the liquid vehicle and the need to evaporate large amounts of solvent. In addition they are subject to process and product variables. Also it is preferable that liquid layering methods are based on aqueous systems; nevertheless organic solvents are often used for those active substances having poor aqueous solubility. A process using organic solvent has disadvantages of high costs, environmental pollution and explosion hazard. Drug state transitions can also occur either during or after the liquid spraying phase. As a result, crystalline drugs once loaded on inert cores, may assume a different crystalline state or even a metastable amorphous state, both altering the drug release profile on storage.
Known powder layering techniques based on drug loading by gravity overcome some of the above-mentioned drawbacks. However limiting factors accompany the use of powder layering such as non-uniform distribution of the drug onto the seeds, and high dust formation during the process which lowers the yields and requires the process to be run discontinuously with intermediate drying. This is necessary to avoid sticking or agglomeration of individual cores. but is very time consuming if an adequately deep layer is to be loaded onto the cores. A typical industrial process may take in the order of 24 hours.
The non-uniform drug distribution gives rise to single loaded units with irregular shape and rough surface and causes an increment of the products surface specific area (SSA). An increase of the SSA means a higher spray volume must be applied to get the desired average thickness. Poor reliability from batch to batch is also associated with such a layering system. Moreover, when coating is based on weight gain, the poor batch reproducibility gives rise to finished products with a variable average film thickness and therefore the resulting units will each have different release profiles. Where a final sealing coating is required, the volume of sealant is increased due to high surface area of the units.
Additionally, known powder layering techniques produce a rather considerable dust formation which tends to be suspended on the air stream during the process. This dust problem is also responsible for cross-contamination and safety hazards for the operators, as well as loss of active substance through the exhaust of the ventilation system.
Another disadvantage of powder layering is that the poor reliability requires time-consuming procedures to get satisfactory results in matter of process validation. This is necessary to meet requirements of medicine control agencies.
There is need therefore for a process for applying a drug or excipient layer to a unit or seed particle with improved layering times over solution/suspension coating techniques.
There is also a need for a process to prepare spherical dosage forms with improved regularity of shape.
Furthermore there is a need for a process for preparing multiple units dosage forms with consistent properties and improved reliability of the units.
The present invention provides a process for applying a layer to a pharmaceutical unit, such as a seed unit or tablet, which comprises:
(a) spraying the unit with dry particles of drug and/or excipient,
(b) applying to the unit a binder comprising solvent, and
(c) drying.
Steps (a) and (b) can be initiated, and/or terminated, sequentially in either order or simultaneously. Generally once the process has started steps (a) and (b) are run simultaneously for sufficient time to load the desired amount of drug onto the pellet. During simultaneous loading (ie steps (a) and (b) running for a period together) it is possible to reach an equilibrium where solvent evaporates or dries at a rate substantially equal to the rate of binder application.
Conveniently the binder is applied before the powder application starts, for example about 20 seconds or less before, eg about 10 seconds before, and is terminated preferably after the powder spraying has stopped to ensure all drug has been applied and to minimise loss. Drying may continue until substantially all solvent is removed.
Powder atomisation ensures a homogeneous drug loading and an enhanced sphericity.
In one aspect of this invention when coating the unit with particles of drug and/or excipient; the unit and the particles are at different electrical potentials such that electrostatic attraction occurs between them;
Optionally, the dry particles may be electrically charged with respect to the unit.
Accordingly this invention also provides a process for applying a layer to a pharmaceutical unit (eg seed or tablet) which comprises:
(a) spraying the unit with dry particles of drug and/or excipient, the unit and the particles being at different electrical potentials such that electrostatic attraction occurs between them;
(b) applying to the unit a binder, and
(c) drying.
As above steps (a) and (b) can be carried out, and/or initiated, sequentially in either order or simultaneously.
Spraying in the manner described herein permits layering to substantially the whole surface of the unit in a single operation.
Electrostatic attraction can minimise dust formation, and thus there is reduced loss of active substance through the exhaust of the ventilation system. Furthermore, the particles are strongly attracted to the seed units, and consequently the volume of particles carried off during evaporation of the binder is reduced. However an electric charge is unsuitable in cases where an organic solvent is used for the binder, and accordingly, in such cases the invention can be used without applying a charge.
The present invention is particularly suitable for the production of pharmaceutical units with high drug loading. Such a method ensures high reliability while improving the productivity in comparison with known powder layering processes. It finds broad applicability on drug loading of inert cores such as non pareils seeds or granules on the manufacturing of multiparticulate dosage forms. Layering of monolithic dosage forms such as tablets is however possible, eg tablets up to about 20 mm in length. Drug particles are sprayed through a nozzle connected with an air flow inlet. Particles are thus atomized onto inert seeds loaded on conventional equipments such as for instance coating pans beds. This system ensures uniform layering, and improved process productivity in comparison with known powder layering techniques based on gravity loading when processing the same quantity of components in the same coating bowl.
Preferably the powder and binder are applied from different directions, or in the same direction but along separate axes. This can avoid over wetting and thus sticking or aggolmeration. As a result process time can be reduced significantly being strictly dependent on spraying rates of powder and binder.
The potential difference between the unit and the particles, if applied, should be sufficiently high to ensure a strong attraction between the two and may conveniently be in the order of from about 50,000 to about 300,000 volts, preferably about 75,000 to 200,000 volts. Since it is not necessary for both the unit and the particles to be electrically charged the process may be conveniently carried out by electrostatically charging one of the unit and the particles. Preferably the particles are electrostatically charged, most preferably with a negative charge.
Preferably the particles are applied by spraying onto a plurality of units in a coating drum. Improved results are obtained where the particles are in the form of a powder with a maximum particle size of about 250 microns or less, preferably about 150 microns or less, most preferably about 100 microns or less.
On startup drug loading is preferably preceded by a wetting of the non pareil seeds ensured by the binder/solvent. In operation the binding solution is preferably sprayed onto the units simultaneously with the application of the powder particles.
The process is particularly suitable for layering units such as non-pareil seeds where the substantially spherical form of the seed is retained to a high degree during layering with the result that each multi-layered dosage unit produced is substantially spherical.
Any suitable binder used in the preparation of pharmaceutical dosage forms can be used including for example polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, polyacrylates, carboxymethyl-cellulose or gelatine or mixtures thereof. Conveniently the binder is dissolved in a solvent to a suitable concentration. Where the powder being applied is sufficiently soluble in water (or other solvent) then the binder solution can consist solely of water (or other solvent) without added ingredient.
In a preferred embodiment this invention provides a process for preparing a multi-layered pharmaceutical seed unit which comprises the following steps:
a) loading inert nonpareil seeds into a suitable coating apparatus optionally electrostatically earthed,
b) dry spraying drug and/or excipient particles optionally electrostatically charged, onto the seeds using a spraying nozzle, while simultaneously applying a binding solution,
c) drying the loaded cores; to provide the multi-layered pharmaceutical seed unit.
This invention also provides apparatus for preparing said layered pharmaceutical seed units.
The apparatus comprises a vessel adapted to receive a seed unit, and loading means for layering said unit with particles, wherein said loading means comprises a powder spraying jet for dry spraying particles at said unit.
Optionally the powder layering may use an electrostatic potential difference to improve particle adhesion. This level of adhesion may be varied by adjusting the electrostatic charge. Preferably a plurality of seed units are provided.
Optionally, the powder layer can be sealed or coated in any known manner for example by using a final spray of liquid sealer, or by incorporating a waxy substance in the powder coating which is softenable on application of heat. The latter method may not be suitable if the active substance is heat sensitive.
Preferably the apparatus includes a fluid binder spray for ensuring adhesion of the particles to the units. Such a spray allows a build up of successive layers of particles on the units. The binder spray may be applied before, during or after spraying of the particles.
Separate spraying of powder and binder allows independent variation of flow rate and spray duration, which may be very useful in controlling process variables and permitting active control of the process according to real time measurements. The binder spray nozzle may also be used for spraying other coatings and/or sealing layers. Independent spray control also facilitates variation of the volume of liquid spray according to need, and to the size and absorbency of the seed units.
Ventilation of the coating vessel is preferred, especially where evaporation of liquid is required. In a preferred embodiment low pressure forced air ventilation is provided, and this allows further process control by variation of air pressure, flow rate and ventilation on/off periods. The ventilation air may also be pre-heated to a desirable level; this allows further control of process variables.
In the preferred embodiment, the layering vessel is a rotatable drum with a substantially horizontal axis in which is arranged a relatively fixed array of powder spraying nozzles. The drum preferably includes internal baffles or strakes to cause the seed units to roll and intermingle. In use rotation of the drum causes a charge of seed units to lie at one side, and preferably the powder spraying nozzles are orientated approximately at right angles to the surface plane of the charge. The orientation of the powder spraying nozzles may be adjustable. Real time adjustment may be provided in any suitable manner, for example by the use of stepper motors, pneumatics or the like.
Binder spray nozzles, where provided. may also have adjustable orientation in real time. The orientation of binder nozzles may be different from that of powder spraying nozzles, and the respective orientation may be independently variable. Where a plurality of nozzles of either type are provided, the nozzles may themselves be independently adjustable for flow rate orientation and spray pattern.
In the case of the rotatable drum, the powder spray nozzles and binder spray nozzles are preferably mounted from an end wall opposite to the usual door in the other end wall. A ventilation inlet duct may extend from one end close to the rotational axis of the drum. Radial duct arms preferably convey ventilation air close to the surface of the charge of seed units so as to blow air over the units. An exhaust outlet is preferably provided in the same end wall as the inlet.
The radial duct arms do not themselves disturb or suspend the seed units, as in prior art arrangements, and these arms may include end openings or diffusers of any suitable design, to ensure adequate air flow over the charge of units.
The distance between the powder spraying nozzles and the charges of seed units may be variable. Preferably this distance is variable in real time to ensure a desirable spraying pattern as the individual units grow in diameter and thus the charge volume increases, typically by 100% or more. The distance may be variable in discrete steps, or may be continuously variable according to desired process parameters. Any suitable means for moving individual nozzles, or a spray bar on which such nozzles are provided, may be adopted. Suitable means may be pneumatic or electrical; however the latter would be unacceptable in the case of solvent based binder sprays because of the risk of explosion. Variation of the distance between the binder spraying nozzles and powder spraying nozzles may be provided. Typically the powder spraying nozzle(s) are(is) from 70 mm to 250 mm in distance from the surface being sprayed, eg about 100 to 150 mm. Typically the binder spraying nozzle(s) are(is) from 150 mm to 450 mm in distance from the surface being sprayed, eg about 250 to 350 mm, preferasble about 300 mm.
The use of separate powder and binder spray nozzles is particularly useful because each can be independently adjusted with respect to orientation, flow rate, spray pattern, on/off time and distance from the units and from each other. This allows very close control of process parameters.
A further advantage of a horizontal axis drum is that a greater charge volume can be processed according to known process variables simply by increasing drum length and incorporating additional nozzles as required. This avoids the prior art solution of increasing drum diameter, which necessarily changes process variables in a manner which may be difficult to predict.
In a further aspect this invention provides a substantially spherical multi-layered dosage unit comprising one or more drugs, preferably having a shape factor (as hereinafter defined) of 0.65 or more; preferably greater than 0.8; most preferably 0.84 or more, e.g. at least 0.88.